Changes in images of brain functional activity that are produced by disease or by activation of various pathways in the normal brain can only be unambiguously interpreted if the rates of the physiological and biochemical processes that underlie the imaging method are quantified. In imaging modalities that use radioactive tracers, e.g. positron emission tomography (PET), quantification is carried out by means of a mathematical model that describes the rates of the biochemical reactions in the metabolic pathway of the tracer and traced molecules. Selection of the best kinetic model is critical as the use of an inappropriate model can lead to substantial errors in quantification and possible misinterpretation of results. Once a model is selected, numerical procedures that are efficient, robust, and require minimal assumptions about the errors in the measurements are required to estimate accurately the parameters. Additionally, powerful statistical tests are needed so that the data can be examined for significant differences among experimental groups. The objective of this project is to develop better techniques for addressing these interrelated mathematical and statistical issues; advances in the current year were made in the following areas: [unreadable] [unreadable] (1) We have validated a method for quantitative determination of regional rates of cerebral protein synthesis (rCPS) with C-11 leucine and PET (see project MH000889). The method uses a kinetic modeling approach to estimate lamda, the fraction of the precursor pool for protein synthesis derived from arterial plasma, in order to correct for recycling of tissue amino acids (Schmidt et al., JCBFM 2005; 25:617-28). Because estimates of kinetic model rate constants decline with time in heterogeneous tissues until all precursor pools equilibrate with arterial plasma (Schmidt et al., JCBFM 1991; 11:10-24), estimated lamda and rCPS may also change with time until equilibrium has been achieved. We have recently undertaken a study to examine the optimal scanning interval measurement of rCPS. Anesthetized monkeys were dynamically scanned for 60 min following injection of C-11 leucine. Kinetic model rate constants and lamda were estimated over varying time intervals for whole brain and several regions of interest, and rCPS was computed. Rate constants and rCPS tended to decrease with increasing estimation interval, indicating that the optimal scanning interval should not be shorter than 60 min. Preliminary results were presented at the Society for Nuclear Medicine 53rd Annual Meeting (SNM2006). In order to determine how much, if any, the scanning interval must be extended beyond 60 min for optimality, 120-min dynamic scans of anesthetized monkeys are now ongoing. [unreadable] [unreadable] (2) Work continued on a study to use detailed distributional data from C-14 leucine autoradiographic studies to estimate the precision of PET measurements with C-11 leucine. We have constructed a three-dimensional volume from C-14 leucine autoradiograms of one hemisphere of a monkey brain, and computationally matched the resolution of this volume to that of the PET scanner. We are developing analysis methods to use this database to estimate the sensitivity of the PET scanner for detecting specific changes in regional rates of cerebral protein synthesis. Partial results were published in Nuclear Medicine and Biology (Schmidt and Smith, NMB 2005; 32:719-725).[unreadable] [unreadable] (3) Development of techniques for assessing changes in serotonin 5HT1A receptor occupancy in rats by use of a small animal PET scanner and a continuous infusion of the 5HT1A receptor antagonist 4-[18F]-fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyrimidinyl)benzamide ([18F]FP-WAY) was completed, and a paper detailing the findings is in press (Tokugawa et al., Eur J Nucl Med and Molecular Imaging).[unreadable] [unreadable] (4) The lumped constant for fluorodeoxyglucose was determined in awake rats by an autoradiographic method employing C-14 fluorodeoxyglucose and C-14 deoxyglucose. The value obtained was 0.71. This result was presented at the Society for Nuclear Medicine 53rd Annual Meeting (SNM2006), and a paper detailing the finding is in press (Tokugawa et al., J Nucl Med).